FTO-mediated m(6)A demethylation regulates IGFBP3 expression and AKT activation through IMP3-dependent P-body re-localisation in lung cancer.

Lung cancer remains one of the leading causes of cancer-related deaths worldwide, and a growing body of evidence suggests that RNA modifications, including methylation, play a critical role in its progression. In this study, we investigated the role of the RNA demethylase fat mass and obesity-associated protein (FTO) in lung cancer progression and determined the underlying molecular mechanisms. FTO expression was significantly upregulated in LUAD and correlated with poor prognosis. FTO knockdown in lung patient-derived organoids and LUAD cell lines reduced their proliferation, invasion, and migration, and FTO knockdown in a Kras(G12D) mouse model reduced the growth of lung tumours. Mechanistically, FTO demethylated m(6)A sites in the insulin-like growth factor-binding protein 3 (IGFBP3) 3'UTR, preventing IMP3 binding. The ribonuclear protein IMP3 was identified as a crucial functional reader that interacted with m(6)A-modified sites in the IGFBP3 3'UTR, thereby promoting IGFBP3 mRNA localisation to P-bodies and suppressing its translation. Elevated IGFBP3 activated AKT signalling and promoted tumour progression. Collectively, we revealed that FTO drives lung cancer progression via m(6)A-dependent sequestration of IGFBP3 mRNA into P-bodies by IMP3, which suppresses translation and activates AKT signalling. The FTO-IGFBP3-AKT axis thus represents a promising therapeutic target. KEY POINTS: FTO regulates the translation of IGFBP3 by demethylating m6A sites in the 3'-untranslated region of IGFBP3 mRNA. Binding of the m6A reader protein IMP3 to 3'UTR m6A sites in IGFBP3 mRNA promoted its localisation and sequestration in cellular organelles known as to P-bodies, thereby suppressing IGFBP3 mRNA translation. IGFBP3 regulates activation of the AKT signalling pathway, and that FTO-mediated regulation of IGFBP3 influences LUAD malignant behaviours.